We have developed an immunotoxin SS1P that targets ovarian cancers, mesotheliomas and pancreatic cancers that is currently in clinical trials. We are now carrying out laboratory experiments to produce improved forms of SS1P. One approach is to modify SS1P with high molecular weight polyethylene glycol to decrease immunogenicity. Many mutants of SS1P have been produced to allow site-specific modification with PEG. Hematopoietic Tumors- Immunotoxin BL22 has shown excellent clinical activity in patients with Hairy Cell Leukemia. To increase the usefulness of BL22 in other leukemias and lymphomas we have mutated the protein to increase its affinity for CD22 and also mutated the toxin to increase its ability to reach the cytosol and kill target cells. An improved form of BL22 called HA22 is being prepared for a clinical trial in chronic lymphocytic leukemia. CD30 is expressed on cells from Hodgkin's disease and anaplastic large cell lymphoma. A series of new antibodies to CD30 have been produced and used to make immunotoxins. These are now being tested in nude mice expressing CD30 positive tumors. 8H9 is a monoclonal antibody developed by Dr. Cheung at Sloan Kettering that targets an antigen expressed on many childhood cancers and breast cancer. We have produced a recombinant immunotoxin that kills cells expressing the 8H9 antigen and this immunotoxin causes tumor regressions in mice with human cancer xenografts.